Astex Pharmaceuticals and Otsuka Announce Results of the Phase 3 ASTRAL-1 Study of Guadecitabine (SGI-110) in Treatment-Naïve AML Patients Ineligible to Receive Intense Induction Chemotherapy

PLEASANTON, Calif. & TOKYO

Astex Pharmaceuticals, a member of the Otsuka group of companies, and Otsuka Pharmaceutical Co. Ltd., announce top-line results from the ASTRAL-1 study evaluating the efficacy and safety of guadecitabine (SGI-110) in adults with previously untreated AML who are not eligible for intensive induction chemotherapy. The study did not meet its co-primary endpoints: complete response (CR) rate (p>0.04), and overall survival (OS) (p>0.01) as per the protocol analysis plan, compared with the control arm of physician’s choice of azacitidine, decitabine, or low dose cytarabine. Evaluation of the study’s secondary endpoints and safety data is ongoing. The full data will be presented at an upcoming scientific meeting.

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The company continues to focus on completing the ongoing global phase 3 ASTRAL-2 and ASTRAL-3 studies evaluating guadecitabine in the treatment of relapsed and refractory AML and relapsed and refractory MDS and CMML.

“We are disappointed in the outcome of the ASTRAL-1 study,” said Mohammad Azab, Astex’s president and chief medical officer. “The study used very strict criteria of ineligibility to receive intensive chemotherapy based on age (over 75 years) or poor performance status (ECOG PS of 2 or 3) or comorbidities, which made it a difficult population to show superior benefit of guadecitabine.” Dr. Azab also added, “ASTRAL-1 is the largest global prospective study ever conducted in this specific patient population with low intensity therapy, with 815 patients randomized, of whom about 90% were treated with hypomethylating agents or HMAs (guadecitabine, azacitidine, or decitabine). The large body of clinical and genetic data will still provide the medical community with very valuable insights into the role of several prognostic clinical and genetic markers that may influence outcome with HMA treatment. We are extremely grateful to all the patients, physicians and other healthcare professionals, and partner research and manufacturing organizations who contributed to this global effort. We are now looking forward to the completion of the ASTRAL-2 and ASTRAL-3 studies currently actively recruiting in two different indications.”

About Guadecitabine (formerly SGI-110)

Guadecitabine is a next-generation DNA hypomethylating agent.^1,2 Guadecitabine was rationally designed to be resistant to degradation by cytidine deaminase, prolonging the exposure of tumor cells to the active metabolite, decitabine, thus ensuring greater uptake of decitabine into the DNA of rapidly dividing cancer cells.³ Guadecitabine, through the action of decitabine, inhibits DNA methyl transferase (DNMT), with the potential to reverse aberrant DNA methylation, an epigenetic change characteristic of many cancer cells that results in silencing of critical genes. This action may restore the expression of silenced tumor suppressor genes and tumor-associated antigens.⁴ Through this re-expression of silenced genes, guadecitabine may have the potential to sensitize tumor cells to other anticancer agents,^5,6,7 including immunotherapeutics,⁸ as well as re-sensitizing cancer cells previously resistant to chemotherapeutics.⁷

Guadecitabine is currently being studied in two additional phase 3 studies:

• ASTRAL-2: A randomized, open-label study in leukemia patients with relapsed or refractory acute myeloid leukemia (AML) following intensive chemotherapy. See www.clinicaltrials.gov NCT02920008.
• ASTRAL-3: A randomized, open-label study in myelodysplastic syndromes (MDS) or chronic myelomonocytic leukemia (CMML) after failure of treatment with azacitidine, decitabine, or both. See www.clinicaltrials.gov NCT02907359.

In addition, guadecitabine is being evaluated in over twenty investigator and company-sponsored trials in other hematological malignancies and in solid tumors, both as a single agent, and in combination with chemotherapy or immunotherapy.

Guadecitabine was designed to be administered subcutaneously as a low-volume, stable formulation.

About the ASTRAL-1 Study

The ASTRAL-1 study evaluated the efficacy and safety of guadecitabine (formerly SGI-110) in adults with previously untreated AML who are not eligible for intensive induction chemotherapy (see www.clinicaltrials.gov NCT02348489). The study is the largest global prospective study ever conducted in this specific patient population, with 815 patients randomized from 163 investigator sites in 24 countries worldwide. The study compared guadecitabine, delivered subcutaneously (SC) 60mg/m²/day for 5 days, with physicians’ choice of azacitidine IV or SC 75 mg/m²/day for 7 days, decitabine IV 20 mg/m²/day for 5 days, or low dose cytarabine SC 20 mg bid for 10 days, all administered in 28-day cycles. In addition to the co-primary endpoints of OS and CR, the study evaluated multiple secondary endpoints including progression-free survival; composite CR or CRc (CR + CRi + CRp); overnight stays in hospital; red cell / platelet transfusions; QOL (EQ-5D-5L); duration of response and safety.

About Acute Myeloid Leukemia

AML is the most common form of acute leukemia in adults.⁹ There were an estimated 21,380 new cases of AML diagnosed in the US in 2017,¹⁰ and an estimate of 10,590 patients were projected to have died from AML in the US in 2017.¹¹ Although 60 to 80 percent of AML patients less than 60 years of age may achieve a complete response (CR) with standard intensive induction chemotherapy,¹² the outlook for patients 60 years of age or more is significantly worse, with response rates less than 50 percent, cure rates following transplant remaining at less than 10 percent and a median survival of less than one year.^12,13,14 These figures have not significantly improved during the last three decades. These patients have few therapeutic options available.^15,16 Effective, less toxic therapies are needed for the treatment of AML, particularly for elderly patients where comorbidities and other consequences of aging may often render them ineligible to receive intensive induction chemotherapy, thus denying them a potentially curative transplant.¹⁴

About Astex Pharmaceuticals and Otsuka Pharmaceutical

Astex is a leader in innovative drug discovery and development, committed to the fight against cancer and diseases of the central nervous system. Astex is developing a proprietary pipeline of novel therapies and has multiple partnered products being developed under collaborations with leading pharmaceutical companies. In October 2013 Astex became a wholly owned subsidiary of Otsuka Pharmaceutical Co. Ltd., based in Tokyo, Japan.

Otsuka Pharmaceutical is a global healthcare company with the corporate philosophy: “Otsuka – people creating new products for better health worldwide.” Otsuka researches, develops, manufactures and markets innovative and original products, with a focus on pharmaceutical products for the treatment of diseases and nutraceutical products for the maintenance of everyday health.

For more information about Astex Pharmaceuticals, please visit http://www.astx.com

For more information about Otsuka Pharmaceutical, please visit http://www.otsuka.com/en/

References

1. Kantarjian HM, Roboz GJ, Kropf PL, et al. Guadecitabine (SGI-110) in treatment-naive patients with acute myeloid leukaemia: phase 2 results from a multicentre, randomised, phase 1/2 trial. Lancet Oncol 2017; 18(10): 1317-26.
2. Roboz GJ, Kantarjian HM, Yee KWL, et al. Dose, schedule, safety, and efficacy of guadecitabine in relapsed or refractory acute myeloid leukemia. Cancer 2018; 124(2): 325-34.
3. Issa JJ, Roboz G, Rizzieri D, et al. Safety and tolerability of guadecitabine (SGI-110) in patients with myelodysplastic syndrome and acute myeloid leukaemia: a multicentre, randomised, dose-escalation phase 1 study. Lancet Oncol 2015; 16(9): 1099-110.
4. Griffiths EA, Choy G, Redkar S, Taverna P, Azab M, Karpf AR. SGI-110: DNA Methyltransferase Inhibitor Oncolytic. Drugs Future 2013; 38(8): 535-43.
5. Kuang Y, El-Khoueiry A, Taverna P, Ljungman M, Neamati N. Guadecitabine (SGI-110) priming sensitizes hepatocellular carcinoma cells to oxaliplatin. Mol Oncol 2015; 9(9): 1799-814.
6. Srivastava P, Paluch BE, Matsuzaki J, et al. Immunomodulatory action of SGI-110, a hypomethylating agent, in acute myeloid leukemia cells and xenografts. Leuk Res 2014; 38(11): 1332-41.
7. Fang F, Munck J, Tang J, et al. The novel, small-molecule DNA methylation inhibitor SGI-110 as an ovarian cancer chemosensitizer. Clin Cancer Res 2014; 20(24): 6504-16.
8. Lindblad KE, Goswami M, Hourigan CS, Oetjen KA. Immunological effects of hypomethylating agents. Expert Review of Hematology 2017; 10(8): 745-52.
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10. Society AC. Key Statistics for Acute Myeloid Leukemia 2018 [Available from: https://www.cancer.org/cancer/acute-myeloid-leukemia/about/key-statistics.html.
11. SEER. Cancer Stat Facts: Leukemia – Acute Myeloid Leukemia (AML) 2018 [Available from: https://seer.cancer.gov/statfacts/html/amyl.html.
12. Dohner H, Estey E, Grimwade D, Amadori S, Appelbaum FR, Buchner T, et al. Diagnosis and management of AML in adults: 2017 ELN recommendations from an international expert panel. Blood. 2017; 129(4):424-47.
13. Burnett A, Wetzler M, Lowenberg B. Therapeutic advances in acute myeloid leukemia. J Clin Oncol. 2011; 29(5):487-94.
14. Dombret H, Gardin C. An update of current treatments for adult acute myeloid leukemia. Blood. 2016; 127(1):53-61.
15. Medeiros BC, Satram-Hoang S, Hurst D, Hoang KQ, Momin F, Reyes C. Big data analysis of treatment patterns and outcomes among elderly acute myeloid leukemia patients in the United States. Ann Hematol. 2015; 94(7):1127-38.
16. Wang R, Zeidan AM, Halene S, Xu X, Davidoff AJ, Huntington SF, et al. Health Care Use by Older Adults With Acute Myeloid Leukemia at the End of Life. J Clin Oncol. 2017; 35(30):3417-24.

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